Extended Release Dosage Form

ABSTRACT

A membrane system comprising an interior wall, a fluid-permeable exterior wall surrounding the interior wall and an internal compartment defined by the membrane system, wherein fluid permeability of the interior wall is responsive to osmolarity of an osmotic core within the internal compartment are disclosed. A controlled release dosage form comprising the membrane system and a process for delivering an osmotically active formulation from an osmotic pump over an extended period of time are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of patent application U.S. Ser. No.09/249,700, filed on Feb. 12, 1999, and international applicationPCT/U.S.99/04192, filed on Feb. 26, 1999, which applications in turnclaim priority from provisional application U.S. Ser. No. 60,077,133,filed Mar. 6, 1998, under 35 U.S.C. § 120.

FIELD OF THE INVENTION

This invention pertains to both a novel and therapeutically usefuldosage form. In particular, the invention relates to a dosage form thatadministers a dose of a therapeutic agent in an extended andlinear-release profile for an indicated therapy. Specifically, theinvention concerns a membrane system comprising an internal compartmentsurrounded by an interior and an external wall, wherein the fluidpermeability of the interior wall is responsive to osmolarity of anosmotic core comprised in the internal compartment. The inventionconcerns also a method of administering the dosage form to provide adose of drug for therapy.

BACKGROUND OF THE INVENTION

To improve the effectiveness of drug therapy and to reduce possiblesystematic side effects, many attempts have been made to deliver drugsin a controlled profile to human patients. The advantage of controlledrelease dosage forms are well-known in both the pharmaceutical andmedical sciences. The therapeutical benefits of controlled-releasedosage forms include the pharmacokinetic ability to maintain apreplanned blood level of an administered drug over a comparativelylonger period of time. The therapeutical benefits include also asimultaneous increase in patient compliance and a reduction in thenumber of doses of drug administered to a patient.

The prior art made available controlled release dosage that sought toprovide a drug release rate profile that matched the blood physiologicaland chrono-pharmacological requirements needed for therapy. For example,U.S. Pat. Nos. 3,845,770 and 3,916,899 issued to Theeuwes and Higuchipertains to an osmotic dosage form for delivering various drugs to apatient environment of use. The dosage forms disclosed in these patentsare manufactured comprising a wall that surrounds a compartmentcomprising a drug with an exit in the wall for delivering the drug to apatient. In U.S. Pat. Nos. 4,008,719; 4,014,334; 4,058,122; 4,116,241;and 4,160,452 patentees Theeuwes and Ayer made available dosage formscomprising an inside and an outside wall made of poly(cellulose acylate)for delivering a dosage of drug to a patient in need thereof.

The history of the prior art dosage forms indicates a serious needexists for a novel and useful dosage form that provides an unexpectedadvancement in the science of dosage forms. For example, the prior artdosage forms lack the present ability to mask an unpleasant taste, theydid not maintain the stability of a drug formulation, and the dosageforms did not protect a drug from oxidation. Then too, the drugformulation in the dosage form permitted the drug release profile todecline over time, thereby administering a nontherapeutic dose of drug.The wall of the dosage forms exposed to the gastrointestinal tract werelipophilic, they absorbed endogenous fats and consequently evidenced adecrease in structural integrity as seen in flaws or cracks in the wall.Moreover, the dosage forms wall and its drug formulation did not act inconcert for providing a controlled linear drug delivery profile over anextended time. Likewise, prior art dosage forms were formulated withwater-leachable components within the membrane to control delivery rateof drug which water-leachable components diffused from the membraneagainst the direction of osmotic water flux making reproducibility andcontrol of delivery rate patterns difficult, as seen in U.S. Pat. No.5,160,744.

It is clear from the above presentation that a long-felt need exists fora dosage form comprising a walled structure and a drug formulation thatfunction together for administering orally a drug at a controlled andsustained-release drug delivery profile with time. The need exists for adosage form for administering a drug in a linear profile for treatinginfectious diseases, respiratory diseases, the cardiovascular system,blood and spleen, the digestive system, metabolic disorders, theendocrine system, the urogenital tract, sexually transmitted diseases,the nervous system, the locomotor system, psychiatric disorders and forproviding symptomatic care. A dosage form is needed for replacingimmediate-release dose-dumping forms administered three or four timesdaily. There are serious reasons for seeking a dosage form that replacesimmediate-release forms, including a means for reducing peak-bloodlevels followed by a sharp drop in blood levels, a means for lesseningside effects, a means for manufacturing the structural integrity of thedosage form, and a means for reducing the number of solvents used tomanufacture the dosage form.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide both a novel and a useful dosageform that overcomes the disadvantages associated with the prior art.

Another object of the present invention is to satisfy a long-felt needby providing a dosage form for controlled delivery wherein a therapeuticagent is administered in a linear profile over an extended period oftime for an indicated therapy.

In one embodiment the invention provides a membrane system comprising aninterior wall surrounding an internal compartment, wherein fluidpermeability of the interior wall is responsive to osmolarity of anosmotic core comprised in the internal compartment; and afluid-permeable exterior wall surrounding the interior wall, wherein theinterior wall and the exterior wall are in contacting relationship. Thewalls of the membrane system maintain its physical and chemicalintegrity during the administration of a drug. Additionally, theexterior wall provides a bioprotective wall that shields the dosage formfrom injury and/or destruction in a gastrointestinal environment.

In preferred embodiments, the interior wall comprises hydrophobic andhydrophilic substance, wherein the hydrophilic substance exhibits anaqueous solubility responsive to osmotic pressure and/or ionic strengthof the osmotic core. In an alternative embodiment, the interior wallcomprises a polymer composition, wherein the hydrophilic substanceexhibits an aqueous solubility responsive to degree of hydration of thepolymer composition.

Another object of this invention is to provide a membrane system whereinthe inside wall comprises a hydrophobic polymer insoluble in thedigestive system and hydrophilic polymer soluble in the digestive systemwherein the hydrophilic polymer enhances the fluid flux of the interiorwall.

In preferred embodiments, the inner wall comprises a member selectedfrom the group consisting of hydrogel polymers, osmopolymers,osmotically-effective compounds, suspending agents, compounds forforming passageway, pore formers polypeptides, proteins,polysaccharides, cellulose derivatives, surfactants, synthetic polymersand inorganic polymers. More preferably, the membrane system comprises ahydrophobic substance comprising ethyl acetate or cellulose acetate; ahydrophobic membrane comprising hydroxyalkylcellulose; and asemipermeable substance comprising cellulose acetate.

The internal compartment membrane system comprises a therapeutic agent.In additional embodiments, the internal compartment further comprises apharmaceutically acceptable osmotically-effective compound andoptionally a pharmaceutically acceptable hydrogel polymer. Inalternative embodiments, internal compartment further comprises anexpandable layer, wherein the expandable layer comprises anosmotically-effective compound.

Another object of the invention is to provide a controlled releasedosage form comprising an osmotic core; an interior wall surrounding theosmotic core, wherein fluid permeability of the interior wall isresponsive to osmolarity of the osmotic core; and a fluid-permeableexterior wall surrounding the interior wall.

Another object of the invention is to provide a controlled releasedosage form comprising an osmotic core; an interior wall in contact withthe osmotic core, wherein fluid permeability of the interior wall isresponsive to osmolarity of said osmotic core; and a fluid-permeableexterior wall in contact with the interior wall.

The osmotic core comprises a therapeutic agent; and further the osmoticcore, the internal wall and the external wall act in concert to providea controlled delivery of the therapeutic agent over an extended orsustained-release period of time, preferably over a period of about 30minutes to about 30 hours, more preferably about 6 hours to about 24hours, and even more preferably about 4 hours to about 24 hours. Theinterior wall, the exterior wall and the osmotic core are as describedin the membrane system above.

Another object of the invention is to provide a transport mechanismwhereby water-soluble flux enhancers within the interior wall, duringthe operation of the dosage form, are transported by diffusion from theinterior wall in the same direction as the osmotic water-flow passingthrough the membrane system.

Another objective of the invention is to provide a controlled releasedosage form, wherein said inner wall comprises a member selected fromthe group consisting of hydrogel polymers, osmopolymers,osmotically-effective compounds, suspending agents, compounds forforming passageway, pore formers polypeptides, proteins,polysaccharides, cellulose derivatives, surfactants, synthetic polymersand inorganic polymers. In a preferred embodiment, the controlledrelease dosage form comprises a hydrophobic substance comprising ethylacetate or cellulose acetate; a hydrophobic membrane comprisinghydroxyalkylcellulose; and a semipermeable substance comprisingcellulose acetate.

Another object of the invention is to provide a process for deliveringan osmotically active formulation from an osmotic pump over an extendedperiod of time comprising: (i) disposing the formulation in an osmoticpump; (ii) exposing the osmotic pump to a fluid environment to causedelivery of the formulation therefrom in response to osmotic imbibitionof fluid into the pump; and (iii) increasing the fluid permeability ofthe pump in response to decreasing osmolarity of the formulation.

The formulation comprises a therapeutic agent, wherein the therapeuticagent is delivered in an extended-linear, non-declining release profileover an extended or sustained-release period of time, preferably over aperiod of about 30 minutes to about 30 hours, more preferably about 6hours to about 24 hours, and even more preferably about 4 hours to about24 hours. The sustained release rate provided by the invention is freefrom changes induced by the environment of the gastrointestinal tract.In a preferred embodiment, the extended-linear release profile is a zeroorder release profile. In an alternative embodiment, the extended-linearrelease profile is an ascending release profile.

Another objective of the invention is to provide a membrane comprising asemipermeable membrane having a control membrane disposed thereon, thewater permeability of the control membrane being responsive to changesin the osmolarity of fluid contacting said control membrane. Thecomposition of the control member corresponds to the composition of theinterior wall as described above. The composition of the semipermeablemembrane corresponds to the composition of the exterior wall asdescribed in the membrane system above.

Another objective of the invention is to provide an osmotic pumpcomprising: an osmotic core; a semipermeable membrane enclosing at aleast a portion of the core; and a control membrane disposed between atleast a portion of the semipermeable membrane and the core, the waterpermeability of the control membrane being responsive to changes in theosmolarity of the core.

Another object of the present invention is to provide a dosage formmanufactured as an osmotic drug delivery device by standardmanufacturing procedures into sizes, shapes and structures thatrepresent an advancement in the drug delivery art.

Another object of the invention is to provide a method for treating apatient with a medication administered from a controlled-release dosageform.

Other objects, features, aspects, and advantages of the invention willbe more apparent to those versed in the drug dispensing art from thefollowing detailed specification taken in conjunction with the Figuresand the accompanying claims.

BRIEF DESCRIPTION OF DRAWINGS

In the Figures, which are not drawn to scale, but are set-forth toillustrate various manufactures of the invention, the Figures are asfollows:

FIG. 1, is a general view of a dosage form provided by this invention,that is designed, shaped and adapted for the oral administration of adrug at a controlled rate over an extended time to a human patient inneed of drug therapy.

FIG. 2, is a general view of the dosage form of FIG. 1, in openedsection, depicting a dosage form provided by this invention comprisingan internally housed pharmaceutically-acceptable drug compositionsurrounded by an interior and exterior wall.

FIG. 3, is an opened view of FIG. 1, illustrating a dosage formcomprising a drug composition, and a separate but initially contactingpush-displacement composition comprising means for pushing the drugcomposition from the dosage form with both compositions surrounded by aninterior wall and an exterior wall.

FIG. 4, is an opened view of the dosage form of FIG. 1, depicting thedosage form in operation as a fluid sensitive pore former begins todissolve, and is eluted from the interior wall to increase the porosityof the interior wall, while simultaneously keeping the physical andchemical integrity of the exterior wall.

FIG. 5, represents a plot of the dissolution of pore former candidatesof the interior wall as a function of osmotic pressure.

FIGS. 6, 7, 8 and 9 illustrate release patterns and comparison releasepatterns for dosage forms with different coating compositions.

In the Figures, and in the specification, like parts and likeingredients, are identified by like numbers. The terms that appearearlier in the specification, and in the description of the Figures, aswell as in embodiments thereof, are further described in thespecification.

DETAILED DESCRIPTION OF DRAWINGS

Turning attention now to the Figures in detail, which Figures areexamples of a dosage form and a drug composition provided by thisinvention, and which examples are not to be construed as limiting theinvention, one example of a dosage form is seen in FIG. 1. In FIG. 1, adosage form 10 is seen comprising a body member 11 that comprises anexterior wall 12. The exterior wall 12 surrounds an interior wall and aninternal compartment, not seen in FIG. 1. Dosage form 10 comprises atleast one exit 13 that connect the exterior environment, such as thegastrointestinal tract of a human patient, with the interior of thedosage form.

Dosage form 10, of FIG. 2, illustrates a dosage form that possessescontrolled-release delivery kinetics. The dosage form delivers a drug,or a drug and its pharmaceutically-acceptable salt to a patient in needof drug therapy. The terms “therapeutic agent” and “drug” as usedinterchangeably herein. The phrase, controlled-release denotes thedosage form provides a linear drug release with time, a zero orderdelivery rate or an ascending release profile of drug. Dosage form 10controls or governs the delivery of drug 14, represented by dots 14,from an internal space or compartment 15. Dosage form 10 delivers drug14 at a measured rate per unit time over an extended orsustained-release period of about 30 minutes to about 30 hours, morepreferably about 6 hours to about 24 hours, and even more preferablyabout 4 hours to about 24 hours.

The dosage forms provided by this invention, are useful for establishingtherapeutic drug levels in the blood, including the plasma, for therapy.Dosage form 10, as seen in the accompanying figures, embraces the shapeof a dosage tablet, and it can embrace the shape of a caplet, or abuccal, or a sublingual dosage form. The sustained-release dosage formof this invention provides extended-continuous delivery greater thanconventional, noncontrolled tablets, or noncontrolled-nonsustainedrelease tablets and/or capsules that exhibit a dose-dumping of theirdrug.

Dosage form 10 of FIG. 2, comprises exterior wall 12 that surroundsinternal compartment 15. Exterior wall 12 comprises totally, or in atleast a part a semi-permeable composition. The semipermeable compositionis permeable to the passage of an aqueous or an aqueous-biological fluidpresent in the gastrointestinal tract, and exterior wall 12 isimpermeable to the passage of drug 14. Exterior wall 12 is nontoxic, andit maintains its physical and chemical integrity during the dispensingtime of drug 14. The phrase “maintains its physical and chemicalintegrity” means the exterior wall 12 does not lose its structure, andit does not undergo a chemical change during the dispensing of drug 14.

Exterior wall 12 comprises a composition that does not adversely affectan animal, a human, or components of the dosage form. Compositions forforming exterior wall 12 are, in one embodiment, comprised of a memberselected from the group consisting a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer. Thesecellulosic polymers have a degree of substitution, DS, on theanhydroglucose unit, from greater than 0 up to 3 inclusive. By “degreeof substitution” is meant the average number of hydroxyl groupsoriginally present on the anhydroglucose unit comprising the cellulosepolymer that are replaced by a substituting group. Representativeexterior wall 12 polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkanylates, mono-, and di- andtricellulose alkinylates. Exemplary polymers include cellulose acetatehaving a DS of up to 1 and an acetyl content of up to 31 weight %;cellulose acetate having a DS of 1 to 2 and any acetyl content of 21 to35%; cellulose acetate having a DS of 2 to 3 and an acetyl content of 35to 44.8%; and the like. More specific cellulosic polymers comprisecellulose propionate having a DS of 1.8, a propyl content of 39.2 to 45%and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate havinga DS of 1.8, an acetyl content of 13 to 15% and a butryl content of 17%to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylateshaving a DS of 2.9 to 3, such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate and cellulosetrioctanoate; celluloses diacylate having a DS of 2.2 to 2.6, such ascellulose disuccinate, cellulose dipalminate, cellulose dioctanoate,cellulose dipentanoate, co-esters of cellulose, such as celluloseacetate butyrate, and cellulose acetate propionate, and blends of theabove.

Additional semipermeable polymers comprise acetaldehydedimethylcellulose acetate; cellulose acetate ethylcarbamate; celluloseacetate methylcarbamate; cellulose diacetate propylcarbamate; celluloseacetate diethylaminoacetate; ethyl acrylate methyl methacrylate,semipermeable polyamide; semipermeable polyurethane; semipermeablesulfonated polystyrene; semipermeable crosslinked selective polymerformed by the coprecipation of a polyanion and polycation, as disclosedin U.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and3,546,876; semipermeable polymers as disclosed by Loeb and Sourirajan inU.S. Pat. No. 3,133,132; semipermeable, lightly crosslinkedpolystyrenes; semipermeable crosslinked poly (sodium styrene sulfonate);semipermeable cross-linked poly(vinylbenzyltrimethyl ammonium chloride);and semipermeable polymers possessing a fluid permeability in the rangeof 2.5×10⁻⁸ to 5×10⁻² (cm²/hr·atm), expressed per atmosphere ofhydrostatic or osmotic pressure difference across the semipermeableexterior wall 12. The polymers are known to the polymer art in U.S. Pat.Nos. 3,845,770; 3,916,899 and 4,160,020; and in Handbook of CommonPolymers, by Scott, J. R. and Roff, W. J. 1971, CRC Press, Cleveland,Ohio. Exterior wall 12, in a present manufacture can be coated from asubstantially single solvent system, such as acetone if coated from asolution, or water if coated as a dispersion.

Dosage form 10 comprises an interior wall 16. The interior wall 16 facesinternal compartment 15, and exterior wall 12. Exterior wall 12comprises a surface that faces the environment of use. Internalcompartment 15 is defined by a bilayer membrane system comprisinginterior wall 16 and exterior wall 12 wherein interior wall 16 andexterior wall 12 are in contacting relationship. The fluid permeabilityof interior wall 16 is responsive to the osmolarity or osmolality offluid contacting the interior wall 16 or the osmotic core within theinternal compartment 15. In preferred embodiments, the fluidpermeability of interior wall 16 increases in response to a decrease inthe osmolarity of the osmotic core. Compositions for forming interiorwall 16 comprise a hydrophobic substance and a hydrophilic substancewherein hydrophilicity of the hydrophilic substance is osmosensitive.Preferably, the hydrophilic substance exhibits an aqueous solubilityresponsive to osmotic pressure and/or ionic strength of the osmoticcore. More preferably, the hydrophilic substance provides increasedpermeability of interior wall 16 in response to a decrease in theosmotic pressure or the ionic strength of the osmotic core. Examples ofhydrophilic substances include, but are not limited to, ethylcellulose.Examples of hydrophilic substances include, but are not limited to,hydroxyalkylcellulose comprising an alkyl of 1 to 5 carbons, e.g.,hydroxypropylcellulose.

In alternative embodiments, the interior wall comprises a polymercomposition, including compositions used for forming exterior wall, asdescribed above. Preferably, the hydrophilic substance exhibits anaqueous solubility responsive to degree of hydration of the polymercomposition.

Additional compositions for forming interior wall 16 include, but arenot limited to, polypeptides; proteins such as gelatin, collagen,keratin, casein, ammonium casein, calcium casein, magnesium casein,potassium casein, sodium casein, zein, and the like; peptides, such ashydrolyzed vegetable protein, hydrolyzed milk protein, and the like;polysaccharides such as acacia gum, agar, dammar gum, gellum gum, guargum, locust bean gum, xanthan gum, tragacanth gum, tamarind gum, ghattigum, konjac gum, carrageenans, laminaran, alginic acid, sodium alginate,calcium alginate, potassium alginate, propylene glycol alginate,ammonium alginate, hyaluronic acid, pectin, amylopectin, arabinoglactan,dextrin, cyclodextrin, maltodextrin, polydextrin, amylase, starch,modified starch, hydroxypropyl starch, starch acetate, starch esters,starch ether-esters, starch ether-hemiacetals, starch phosphate, starchsodium octenyl succinate, starch sodium succinate, sodium starchglycolate, starch graft copolymer, pregelatinized starch, furcellaran,n-vinyl lactam polysaccharides and the like; cellulose derivatives suchas sodium carboxymethylcellulose, potassium carboxymethylcellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, low-substitutedcellulose acetate, cellulose sulfate, cellulose phosphate, hydroxyethylmethylcellulose, chitosan, derivatized chitin, hydroxyethylchitin andthe like; surfactants such as sorbitan fatty acid esters,polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters,glycerol monostearate, acetylated monoglycerides, polyethoxylated castoroil, polyoxyethylene polyoxypropylene copolymer, cetostearyl alcohol,ethoxylated mono and diglycerides, lecithin, hydroxylated lecithin,polyethylene glycol stearate, and the like; synthetic polymers such aspolyacrylic acid, sodium polyacrylic acid, potassium polyacrylic acid,polyvinyl alcohol, polyvinyl acetate phthalate, poly(hydroxyalkylmethacrylate), polyethylene glycol, polyoxyethylene, polyvinylpyrrolidone, vinyl pyrrolidone vinyl acetate copolymer, sodiumpoly(vinylsulfonic acid), ammonium poly(vinylsulfonic acid),poly(stryrenesulfonic acid, sodium poly(systrenesulfonic acid),potassium poly(styrene sulfonic acid), poly(vinylphosphonic acid) salts,poly(maleic acid), poly(4-vinylbenzoic acid) salts,poly(3-vinyloxypropane-1-sulfonic acid) salts, poly(4-vinylphenol)salts, poly(n-vinylsuccinamidic acid) salts, polyacrylamides,polyamines, polyimines, and the like; inorganic polymers such asaluminium hydroxide, bentonite, hectorite, laponite, poly(silicic acid),sodium poly(silicic acid), potassium poly(silicic acid), and the like;eucheurn, fucoidan, hypnea and glycyrrhizin.

Additional compositions for forming interior wall 16 include hydrogelpolymers, expandable osmopolymers, osmotically effective compounds,suspending agents, compounds for forming passageway and pore formers asdefined in greater detail below.

In a preferred embodiment, as illustrated in FIG. 2, interior wall 16comprises ethylcellulose, one hundred weight percent, (100 wt %), or inanother manufacture a composition comprising a blend of 40 to 99 wt %ethylcellulose and 1 to 60 wt % hydroxyalkylcellulose with the totalweight of the compositional blend equal to 100% wt. The ethylcelluloseused for the interior wall is nontoxic, insoluble in water, andinsoluble in gastrointestinal fluid. The interior ethylcellulose wall iscoated from a single anhydrous solution, or the interior ethylcellulosewall is coated from a dispersion comprising the single solvent water.The ethylcellulose used for the purpose of this invention comprises a 15to 60 wt % ethoxy content, a viscosity of 4 to 200 centiposes, orhigher, and a 5,000 to 1,250,000 weight average molecular weight. Thehydroxypropylcellulose is homogeneously blended with the ethylcellulose,and is identified by a wavy line 17 in interior wall 16. Thehydroxypropylcellulose 17 in interior wall 16 comprises a 7,500 to1,500,000 weight-average molecular weight, and it is soluble in waterbelow 40° C. and in ethyl alcohol and displays a solubility in waterwhich sensitive to osmotic pressure or ionic strength.

Interior wall 16 comprising hydroxypropylcellulose provides unexpectedproperties for this invention. For instance, ethylcellulose ishydrophobic and accordingly its fluid permeability is low which hindersufficient water flux passing through interior wall 16 to provide awide-range of delivery rates. This invention, enhances the fluidpermeability of interior wall 16 by blending a hydrophilic substance,such as a fluid flux enhancer, wherein hydrophilicity of the hydrophilicsubstance is osmosensitive. Preferably, the hydrophilic substanceexhibits an aqueous solubility responsive to osmotic pressure and/orionic strength of the osmotic core. More preferably, the hydrophilicsubstance increases the permeability of the interior wall 16, e.g.,ethylcellulose wall, in response to a decrease in the osmotic pressureor the ionic strength of the osmotic core. In certain embodiments, asthe hydrophilic substance is dissolved and/or leached from the interiorwall 16, it provides fluid-control pores, resulting in increasedpermeability of interior wall 16. In alternative embodiments, thehydrophilic substance exhibits an aqueous solubility responsive todegree of hydration of the polymer composition.

If the dosage form is manufactured with a single wall comprising acomposition of ethylcellulose and hydroxypropylcellulose, as the poresare formed, the pores allow lipids which are present in thegastrointestinal tract to sorb into this unprotected wall, which leadsto an unaccepted change in this nonprotected single wall. That is, thehydrophobic lipids cause the unprotected wall to become soft, flaccidand tearable as the lipid functions as a plasticizer within theethylcellulose. The presence of the sorbed lipids cause the porous wallto become hydrophobic again, thereby reversing the desirable effects ofthe hydrophilic flux enhancer. The present invention unexpectedlydiscovered by providing an outside wall comprising a cellulose acylate,the outside wall excludes and prevents the lipids of thegastrointestinal tract from contacting and reaching the interior wall.The membrane system provides a wide range of low to high fluxes. In apreferred embodiment, the membrane system comprises an interior wallcomposed of ethylcellulose and hydroxypropylcellulose and an exteriorwall comprised of cellulose acylate. In an alternative embodiment, themembrane system comprises an interior wall composed of cellulose acylateand hydroxypropylcellulose and an exterior wall comprised of celluloseacylate. An additional advantage provided by the present invention iseach wall can be coated from a single solvent to provide reproducibleinterior and exterior walls with reproducible permeability andmechanical properties.

In FIG. 2, internal compartment 15 comprises a single homogenouscomposition. The compartment 15 comprises therapeutic agent 14,represented by dots. The term therapeutic agent as used herein includedmedicines or drugs, nutrients, vitamins, food supplements, and otherbeneficial agents that provide a therapeutic or a benefit to animals,including a warm-blooded animal, humans, farm animals, and zoo animals.Representative of drugs 14 comprises an opioid analgesic selected fromthe group consisting of alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine bezitramide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,diepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazone, ethoheptazine, ethylmethylthiambutene, ethylmorphine,propylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroenitabas, hydrocypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphone,phenazocine, phenoperidine, piminodine, pirtramide, propheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, andtilidine. The dose of opioid drug 14 is 0.1 μg to 700 mg. Additionalexamples of therapeutic agents for use in the instant invention aredescribed in U.S. Pat. No. 5,082,668, which is incorporated herein byreference.

The opioid analgesic 14 can be present in compartment 15 alone, or theopioid analgesic 14 can be present with a nonopioid analgesic 14.Examples of nonopioid analgesic comprise a member selected from thegroup consisting of acetaminophen, aminobenzoate potassium,aminobenzoate sodium, aspirin, benoxaprofen, benzydamine, bicifadinedecibuprofen, fenoprofen, flurbiprofen, ibufenac, indoprofen, ibuprofen,ketoprofen, naproxen, naproxol, salicylamide, sodium salicylate, andsalicylate potassium. The dose of nonopioid analgesic 14 is 0.5 mg to600 mg. An analgesic composition in compartment 15 comprises 1.0 mg to750 mg of both the opioid analgesic and nonopioid analgesic.

The analgesic drug comprising the opioid analgesic and the nonopioidanalgesic can be present as the free base, free acid, or as atherapeutically acceptable derivative, or as a therapeuticallyacceptable salt. The therapeutically acceptable salts comprise inorganicsalts, organic salts, including hydrobromide, hydrochloride, mucate,N-oxide, sulfate, acetate, phosphate dibasic, phosphate monobasic,acetate trihydrate, bi(heptafluorobutyrate), bi(methylcarbamate),bi(pentafluoropropionate), bi(pyridine-3-carboxylate),bi(trifluoroacetate), bitartrate, chlorhydrate, and sulfatepentahydrate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate,triethiodide, benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, and procaine, aluminum, calcium, lithium,magnesium, potassium, sodium propionate, zinc, and the like.

Dosage form 10, in compartment 15 comprises a pharmaceuticallyacceptable polymer hydrogel 18, as represented by horizontal dashes.Representative polymer hydrogels comprise a maltodextrin polymercomprising the formula (C₆H₁₂O₅)λ.H₂O, wherein λ is 3 to 7,500, and themaltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by poly(ethyleneoxide) and poly(propylene oxide) having a 50,000 to 750,000weight-average molecular weight, and more specifically represented by apoly(ethylene oxide) of at least one of 100,000, 200,000, 300,000, or400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium, lithium, potassiumor calcium, and alkyl is 1 to 5 carbons such as methyl, ethyl, propyl orbutyl of 10,000 to 175,000 weight-average molecular weight; and acopolymer of ethylene-acrylic acid, including methacrylic and ethacrylicacid of 10,000 to 1,500,000 number-average molecular weight. Thetherapeutic composition comprises 5 to 400 mg of a polymer hydrogel. Thetherapeutic composition can be manufactured into dosage form 10 and itcan be used as the therapeutic composition for its therapeutic effect.The hydrogel polymer exhibits an osmotic pressure gradient acrossbilayer interior wall and exterior wall thereby imbibing fluid intocompartment 15 to form a solution or a suspension comprising drug 14that is hydrodynamically and osmotically delivered through a passagewayfrom dosage form 10.

Dosage form 10 comprises a binder 19 represented by vertical dashes 19.The binder imparts cohesive qualities to the composition. Representativematerials useful for this invention as binders comprise a memberselected from the group consisting of starch, gelatin, molasses, a vinylpolymer comprises 5,000 to 350,000 viscosity-average molecular weight,represented by a member selected from the group consisting ofpoly-n-vinylamide, poly-n-vinylacetamide, poly(vinyl pyrrolidone), alsoknown as poly-n-vinylpyrrolidone, poly-n-vinylcaprolactone,poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidonecopolymers with a member selected from the group consisting of vinylacetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate,vinyl laureate, and vinyl stearate, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, and mixtures ofbinders. The binders can be used as a solution, or in a dry form toprepare the therapeutic composition. The therapeutic compositioncomprises 0 to 100 mg of a binder and in a present manufacture from 0.01to 50 mg of the binder.

Dosage form 10 comprises a lubricant 20 represented by the letter v. Thelubricant is used during manufacture of the composition to preventsticking to die walls or punch faces, generally to lessen adhesion. Thelubricants are selected from the group consisting of polyethyleneglycol, sodium stearate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, magnesium palmitate, calcium stearate, zincstearate, magnesium stearate, magnesium oleate, calcium palmitate,sodium suberate, potassium laureate, stearic acid, salts of fatty acids,salts of alicyclic acids, salts of aromatic acids, oleic acid, palmiticacid, a mixture of a salt of a fatty, alicyclic or aromatic acid, and amixture of magnesium stearate and stearic acid. The amount of lubricantin the therapeutic composition is 0.01 to 20 mg.

FIG. 3 depicts dosage form 10 in opened section illustrating internalcompartment 15. Internal compartment comprises the therapeuticcomposition containing drug 14, as described in detail in FIG. 2. Thetherapeutic composition of FIG. 2 is identified further in FIG. 3 asdrug layer 21. Drug layer 21 comprises the ingredients described in FIG.2 and the details previously disclosed are included in this descriptionof FIG. 3. Drug layer 21 in FIG. 3 initially is in contact with pushlayer 22.

In FIG. 3, an expandable layer, alternatively referred to as a pushlayer 22 comprises 10 mg to 400 mg of an expandable osmopolymer 23represented by squares. The osmopolymer 23 in layer 22 possesses ahigher molecular weight than the hydrogel polymer 18 in the drugcomposition. The osmopolymer 23 comprises a member selected from thegroup consisting of a polyalkylene oxide and, a carboxyalkylcelluloseand acrylates. The polyalkylene oxide possesses a 1,000,000 to10,000,000 weight-average molecular weight. Representative ofpolyalkylene oxide include a member selected from the group consistingof polymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 molecular weight, polyethyleneoxide possessing a 2,000,000 molecular weight, polyethylene oxidecomprising a 3,000,000 to 8,000,000 molecular weight, polyethylene oxidecomprising a 7,000,000, and 7,800,000 molecular weight, and cross-linkedpolymethylene oxide possessing a 1,000,000 molecular weight, andpolypropylene oxide of 1,200,000 molecular weight. Typical osmopolymer23 carboxyalkylcellulose in the expandable layer 22 comprises a 200,000to 7,250,000 weight-average molecular weight. Representativecarboxyalkylcellulose comprises a member selected from the groupconsisting of alkali carboxyalkylcellulose, sodiumcarboxymethylcellulose, lithium carboxyethylcellulose, calciumcarboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxyalkylhydroxy-alkylcellulose,sodium carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethylcellulose, carboxethylhydroxyethylcellulose andcarboxymethylhydroxypropylcellulose. Typical osmopolymer 23 acrylatescomprise non-crosslinked polyacrylic acid, and polyacrylic acidscrosslinked with allyl sucrose, allylpentacrythritol, or divinyl glycol,sodium or potassium polyacrylic acid, and the like. The osmopolymersused for the push-expandable layer exhibit an osmotic pressure gradientacross semipermeable exterior wall 12. The osmopolymers imbibe fluidinto dosage form 10, thereby swelling, expanding as a hydrogel orosmogel, whereby, they push the drug from the osmotic dosage form.

Push layer 22 comprises 0 to 200 mg, and presently 0.5 to 75 mg of anosmotically effective compound 24, represented by circles. Theosmotically effective compounds are known also as osmagents and asosmotically effective solutes. They imbibe an environmental fluid, forexample, from the gastrointestinal tract, into dosage form 10 forcontributing to the delivery kinetics of push layer 22 and to thepermeability characteristics of the interior wall 16. Representative ofosmotically active compounds comprise a member selected from the groupconsisting of osmotic salts, such as sodium chloride, potassiumchloride, magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,osmotic carbohydrates; glucose, fructose, maltose and sorbitol; urea;osmotic acids; tartaric acid; citric acid; potassium acid phosphate; anda mixture of sodium chloride and urea.

Push layer 22 comprises 0 to 75 mg of a suspending agent used forproviding stability and homogenicity to push layer 22. Suspending agent25, represented by clear triangles comprises ahydroxypropylalkylcellulose that comprises an alkyl of 1 to 7 carbons,straight or branched, with the hydroxypropylalkylcellulose possessing a9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkyl-cellulose is represented by a member selected fromthe group consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropylisopropyl-cellulose,hydroxypropylbutylcellulose and hydroxypropylpentylcellulose. Push layer22 optionally comprises a hydroxyalkylcellulose, also represented bytriangles 25. The hydroxyalkylcellulose is a viscosity-increasingsuspending agent comprises a member selected from the group consistingof hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloseand hydroxybutylcellulose comprising a 7,500 to 1,000,000viscosity-average molecular weight. The suspending agent include alsopolyvinylpyrrolidone, acacia, agar, locust bean gum, alginic acid, gumkaraya, gum tragacaroth, carrageenan, gum ghatti, guar gum, xanthan gum,and bentonite.

Push layer 22 comprises 0 to 5 mg of a nontoxic colorant, or dye 26identified by a half-circle. The colorant 26 makes the dosage form moreesthetic in appearance, and it serves to identify the dosage form duringmanufacture and during therapy. The colorants include Food and DrugAdministrations Colorant (FD&C), such as FD&C No. 1 blue dye, FD&C No. 4red dye, FD&C yellow No. 5, FD&C yellow No. 6, FD&C blue No. 2, FD&Cgreen No. 3, FD&C cranberry red No. 40, red ferric oxide, yellow ferricoxide, black ferric oxide, titanium dioxide, carbon black, Opadry®comprising polycellulose, or starch, or cured polymers with dyescommercially available from Colorcon Corporation, West Point, Pa.;erythrosine, allura red, sunset yellow and chlorophylls.

A lubricant 27, identified by hexagon is formulated into push-expandablelayer 22. Typical lubricants comprise a member selected from the groupconsisting of polyethylene glycol, sodium stearate, potassium stearate,magnesium stearate, stearic acid, calcium stearate, sodium oleate,calcium palmitate, sodium laurate, sodium ricinoleate, potassiumlinoleate, glyceryl monstearate, glyceryl palmitostearate, halogenatedcastor oil, sodium lauryl sulfate, sodium stearyl fumarate, and zincstearate. The amount of antiadherent lubricant in layer 22 is 0.01 to 10mg.

An antioxidant 28, represented by right slanted dashes, is present inpush-expandable formulation 22 to inhibit the oxidation of ingredientscomprising expandable formulation 22. Expandable formulation 22comprises 0.00 to 5 mg of an antioxidant. Representative antioxidantscomprise a member selected from the group consisting of absorbic acid,ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium ascorbate,sodium bisulfate, sodium metabisulfate, sorbic acid, potassiumascorbate, vitamin E, 4-chloro-2-,6-ditertiary butylphenol,alphatocopherol, and propylgallate. The antioxidant slow, or prevent theoxidization of the dosage form and its ingredients by atmosphericoxygen.

Dosage form 10, comprises another manufacture provided by the invention.Dosage form 10 comprises an overcoat not shown on the outer surface ofexterior wall 12 of dosage form 10. The overcoat is a therapeuticcomposition comprising 0.5 to 200 mg of drug and 0.5 to 275 mg of apharmaceutically acceptable carrier selected from the group consistingof alkylcellulose, hydroxyalkylcellulose andhydroxypropylalkyl-cellulose. The overcoat is represented bymethylcellulose, hydroxyethylcellulose, hydroxybutylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxypropylethylcellulose and hydroxypropylbutylcellulose. Theovercoat, carried by the outer surface of the exterior wall 12 distantfrom the compartment 15 and it can be formulated with 0 to 50 wt % of aplasticizer, opacificer, colorant, or antitack agent, not seen in FIG.4. The overcoat provides therapy immediately as the overcoat dissolvesor undergoes dissolution in the presence of gastrointestinal fluid andconcurrently therewith delivers the drug into the gastrointestinal tractfor immediate drug therapy.

Dosage form 10, manufactured as an osmotically controlled-release dosageform, comprises at least one passageway 13. The phrase“controlled-release” as used herein indicates that control is exercisedover both the duration and the profile of the drug release pattern.Preferably, the therapeutic agent is delivered in an extended-linear,non-declining release profile over a period of about 30 minutes to about30 hours, more preferably about 6 hours to about 24 hours, and even morepreferably about 4 hours to about 24 hours. In preferred embodiments,the extended-linear release profile is a zero order release profile. Inan alternative embodiment, the extended-linear release profile is anascending release profile. An ascending release profile is preferredwhen delivering drugs that are not well absorbed in the lowergastrointestinal tract as compared to the upper tract. Thus the higherdrug delivery rate at later hours compensates for the lower absorptionto result in more even plasma concentrations.

The expression “passageway” as used for the purpose of this invention,includes aperture, orifice, bore, pore, porous element through whichdrug 14 can be pumped, diffuse or migrate through a fiber, capillarytube, porous overlay, porous insert, microporous member, and porouscomposition. The passageway 13 includes also a compound that erodes oris leached from exterior wall 12 in the fluid environment of use toproduce at least one passageway. Representative compounds for forming apassageway include erodible poly(glycolic) acid, or poly(lactic) acid inthe wall; a gelatinous filament; a water-removable poly(vinyl alcohol);leachable compounds such as fluid-removable pore-formingpolysaccharides, acids, salts, or oxides. A passageway can be formed byleaching a compound from exterior wall 12, such as sorbitol, sucrose,lactose, maltose or fructose, to form a controlled-release dimensionalpore-passageway. The passageway can have any shape, such as round,triangular, square and elliptical, for assisting in thecontrolled-metered release of drug 14 from the dosage form. The dosageform can be manufactured with one or more passageways for example twopassageways, in spaced-apart relation on one or more surfaces of thedosage form. A passageway and equipment for forming a passageway aredisclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 by Theeuwes andHiguchi; in U.S. Pat. No. 4,063,064 by Saunders et al.; and in U.S. Pat.No. 4,088,864 by Theeuwes et al. Passageways comprisingcontrolled-release dimensions sized, shaped and adapted as areleasing-pore formed by aqueous leaching to provide a releasing-pore ofa controlled-release rate are disclosed in U.S. Pat. Nos. 4,200,098 and4,285,987 by Ayer and Theeuwes.

FIG. 4 illustrates dosage form 10 in operation during a drug 14 deliveryperiod. The illustrated dosage form 10 comprises an exterior wall 12 andan interior wall 16. The exterior wall 12 maintains its physical andchemical integrity throughout the drug delivery period. Interior wall 16comprises a hydrophilic substance 29, for example, a pore former, thatis aqueous soluble at an osmotic pressure of 8 atmospheres, which 8atmospheres generally is the osmotic pressure of the gastrointestinaltract of a human. The hydrophilic substance 29, in one manufacture, is apharmaceutically acceptable polymer that exhibits an aqueous solubilitywhich is sensitive to osmotic pressure, which polymer is soluble at lowosmotic pressure and insoluble or slowly soluble at higher osmoticpressure. Representative of other acceptable hydrophilic substances,also referred to as pore formers, include alkali metal salts such aslithium carbonate, sodium chloride, potassium chloride, and potassiumsulfate; alkaline earth metal salts such as calcium phosphate, andcalcium nitrate; transition metal salts such as ferric chloride, ferroussulfate, and zinc sulfate; polysaccharides including mannitol, mannose,galactose, aldohexose, altrose, talose and sorbitol. The osmoticpressure can be measured by Model 302B, Vapor Pressure Osmometer,manufactured by the Hewlett Packard, Co., Avondale, Pa. A hydrophilicsubstance, e.g., a pore forming polymer, is represented byhydroxypropylcellulose possessing a weight-average molecular weight of80,000 grams per mole. Dosage form 10, when initially placed into anaqueous environment, or into a fluid biological environment, exhibits aslow drug delivery until pore former 29 dissolves or is leached frominterior wall 16. For example, after a period of time, often 1 to 2 hrs,the osmotically-sensitive hydrophilic substance 29 begins to dissolveand is eluted from interior wall 16. This operation, provides acontinuous and seamless interior wall 16 with hydrophilic substance 29being hydrodynamically and osmotically pumped as seen by multi-arrows 30from dosage form 10. The eluted hydrophilic substance 29 causes thepermeability of interior wall 16 to increase, which correspondinglycauses the net permeability of bilaminated interior wall 16-exteriorwall 12 to increase over time. This unexpected result provided by thisinvention, with its increase in permeability offsets any decrease inosmotic activity and produces a linear drug delivery profile. Inpreferred embodiments, the drug delivery profile is a zero order releaseprofile. In an alternative embodiment, the drug delivery profile is anascending release profile.

The permeability of a wall can be measured according to a procedurewhich involves measuring the flow of water through the membrane as aresult of osmotic driving force. The measurement is first conducted witha single layer membrane which represents the exterior wall, then themeasurements are conducted with bilayer membranes with the exterior andinterior walls in parallel arrangement. First, an exterior wall membraneis clamped in a vertical orientation between the two chambers which arecommonly referred to as Franz cells. One chamber is filled withdistilled water which has an osmotic pressure of zero while theadjoining chamber is filled with a solution of known osmotic pressure,such as a saturated solution of potassium chloride which has an osmoticpressure of 245 atmospheres or of saturated lactose solution which hasan osmotic pressure of 20 atmospheres. The osmotic pressure of suchosmotic reference solutions are measured using standard freezing pointdepression measurements or vapor pressure osmometry. Vapor pressureosmometers are available, for example, from Knauer & Co GMBH, Berlin,West Germany. The membrane is thus exposed on one side to pure water andexposed to the osmotic reference solution on the opposite side. Prior tomaking measurements, a graduated pipette is attached to the chamberholding the osmotic reference solution. Both chambers also containmagnetic stirrers and both chambers are also immersed in a thermaljacket. While measurements are taken, both cells are stirred by way ofan external magnetic stirrer and both are maintained at a fixedtemperature. The fixed temperature is maintained by continuously passinga thermostated fluid, such as water at 37° centigrade, through thethermal jacket. The Franz cells and stirring equipment are availablefrom Crown Glass Company, Somerville, N.J.

Water is imbibed by osmosis from the pure water side through themembrane to the solution side. The rate of water flowing through themembrane is measured by monitoring the volumetric flow as a function oftime as reflected in the rise in column of solution within the graduatedpipette. The thickness and exposed surface area of the membrane are alsomeasured. These dimensional measurements are performed with standardmeasuring instruments such as with calipers or a tool maker'smicroscope. Then, given the volumetric flow rates and thesemeasurements, the osmotic permeability of the external wall, K_(e), iscalculated according to the following Equation as: $\begin{matrix}{K_{e} = \frac{\left( {{\mathbb{d}V}/{\mathbb{d}t}} \right) \cdot h_{e}}{\Pi\quad A}} & (1)\end{matrix}$where (dV/dt) is volumetric flow rate, h_(e) is membrane thickness ofthe exterior wall, Π is osmotic pressure, and A is membrane area.

After the permeability of the exterior wall is determined, the membranesystem is then mounted in the Franz cell. The membrane system isoriented such that the interior wall faces the osmotic referencesolution and the exterior wall faces the pure water reference. Theosmotic water flux is then measured across the bilayer membraneaccording to the above procedures. The osmotic water flux is inverselyproportion to the series resistance provided by the exterior wall andthe interior wall and directly proportional to the osmotic pressure, asdescribed by Equation 2: $\begin{matrix}{{{\mathbb{d}V}/{\mathbb{d}t}} = \frac{\Pi}{\left( {{h_{e}/K_{e}}A} \right) + \left( {{h_{i}/K_{i}}A} \right)}} & (2)\end{matrix}$where h_(e) is thickness of exterior wall, K_(e) is permeability ofexterior wall, h_(i) is thickness of interior wall, and K_(i) ispermeability of interior wall. Rearranging Equation 2 yields thepermeability of the interior wall, Equation 3: $\begin{matrix}{K_{i} = \frac{h_{i}\left( {{\mathbb{d}V}/{\mathbb{d}t}} \right)}{\left\lbrack {{\Pi\quad A} + {\left( {h_{e}/K_{e}} \right)\left( {{\mathbb{d}V}/{\mathbb{d}t}} \right)}} \right\rbrack}} & (3)\end{matrix}$

Given the measured values of volumetric flow rate, thicknesses of theinterior wall and exterior wall, the known value for the permeability ofthe exterior wall, and measured osmotic pressure, the permeability ofthe interior wall is then calculated from Equation 3. Osmotic referencevalues of various values ranging from 0 as represented by distilledwater to 445 atmospheres as represented by saturated aqueous ureasolution can be tested in this format to characterize the effect ofosmotic pressure on the permeability of the membrane system. In additionto osmotic pressure, the effect of ionic strength on the permeability ofthe bilayer system can be measured. The measurements, in this instance,performed with reference solutions of known ionic strength against thedistilled water reference as above. The ionic strength of the solution,μ, can be calculated according to standard equations of physicalchemistry such as Equation 4:μ=0.5[C ₁ Z ₁ ² +C ₂ Z ₂ ² +C ₃ Z ²+ . . . ]  (4)where C_(x) represents the molar concentration of any ion x in thesolution and Z_(x) represents the corresponding valence of ion x.Reference solutions of a simple salt such as sodium chloride can beprepared as the ionic strength reference. Since the value of each ioniccharge Z is unity for sodium chloride, a value of one for the sodium ionand a value of one for the chloride ion, the ionic strength according toEquation 4 is directly proportional to molar concentration. A saturatedsolution of sodium chloride consists of 5.5 moles per liter andtherefore has an ionic strength of 5.5 moles per liter. Such a saturatedsolution can be serially diluted with distilled water to produce aseries of ionic strength reference solutions of any value less than 5.5moles per liter for use in the reference cell to determine the effect ofionic strength on the permeability of a membrane system as a function ofionic strength.

Hydrophilic materials for use in forming the interior wall which havesolubilities sensitive to osmotic pressure or to ionic strength can bescreened experimentally prior to formulating them within the interiorwall. This procedure involves forming an aqueous solution of thecandidate hydrophilic materials using distilled water as the solvent.Then, the resulting solution is cast onto a smooth inert surface, suchas a glass plate, and allowed to dry to a film. The film is then removedand cut into sections of known area, thickness, and weight. Theresulting film samples are then placed in a series of referencesolutions of various osmotic pressures or ionic strengths with mildstirring. The time required for the film to dissolve, t, is thenmeasured as a function of osmotic pressure or ionic strength. Then,given the known values of initial film thickness, h_(i), the dissolutionrate of the film, dh/dt, can be calculated according to Equation 5. Thefactor 2 is introduced to account for simultaneous dissolution from bothsides of the film.dh/dt=h _(i)/2t  (5)This screening can also be expanded to include the effect of molecularweight of the hydrophilic material on dissolution rate as a function ofosmotic pressure or ionic strength. This can be accomplished bydetermining the dissolution rate of low molecular weight and highmolecular weight pore formers which effect generally follows the trendof faster dissolution rate at lower molecular weight and fasterdissolution rate at lower osmotic pressure.

FIG. 5 demonstrates the dissolution behavior in the presence of osmoticpressure. The x-axis refers to the osmotic pressure of the test mediaand the y-axis represents the dissolution rate of hydrophilic materialsunder the influence of osmotic pressure. The different symbols representdifferent molecular weight hydrophilic materials initially presentwithin an internal wall. The dark circle represents 80,000 g/mole, theclear circle 190,000 g/mole, the dark triangle 300,000 g/mole, and theclear triangle 1,000,000 g/mole.

In one embodiment, the invention provides a membrane comprising asemipermeable membrane having a control membrane disposed thereon,wherein the water permeability of the control membrane is responsive tochanges in the osmolarity of fluid contacting the control membrane.Preferably, the water permeability of the control membrane is inverselyproportional to changes in the osmolarity of fluid contacting thecontrol membrane. The composition of the control member corresponds tothe composition of the interior wall as described above. The compositionof the semipermeable membrane corresponds to the composition of theexterior wall as described in the membrane system above.

In an alternative embodiment, the invention pertains to an osmotic pumpcomprising an osmotic core; a semipermeable membrane enclosing at aleast a portion of the core; and a control membrane disposed between atleast a portion of the semipermeable membrane and the core, the waterpermeability of the control membrane being responsive to changes in theosmolarity of the core. Preferably, the water permeability of thecontrol membrane is inversely proportional to changes in the osmolarityof the core. The composition of the control member corresponds to thecomposition of the interior wall as described above. The composition ofthe semipermeable membrane corresponds to the composition of theexterior wall as described in the membrane system above.

DESCRIPTION FOR MANUFACTURING THE COMPOSITION AND DOSAGE FORM OF THEINVENTION

The interior wall 16 and the exterior wall 12 of the dosage form can beformed by using an air suspension procedure. This procedure consists insuspending and tumbling a wall-forming composition in a current of airand wall-forming composition until a wall is applied to the drug-formingcompositions. The interior wall is formed first followed by the exteriorwall. The air suspension procedure is well-suited for independentlyforming an individual wall. The walls can be formed with a wall-formingcomposition in a Wurster® air suspension coater. The interior wall canbe formed using the solvent ethanol. The exterior wall is formed usingan organic solvent, such as acetone-water cosolvent 90:10 to 100:0(wt:wt) and with 2.5 wt % to 7 wt % polymer solvents. An Aeromatic® airsuspension coater can be used for applying both the walls, the interiorwall and the exterior wall in successive applications.

Other forming technologies, such as pan coating, can be used forproviding the dosage form. In the pan coating system, wall-formingcompositions are deposited by successive spraying of the composition orthe membrane system, accompanied by tumbling in a rotating pan. A largervolume of cosolvent can be used to reduce the concentration of polymersolids to produce a thinner wall. Finally, the walls of the coatedcompartments are laser or mechanically drilled, and then dried in aforced air or humidity oven for 1 to 3 days or longer to free thesolvent from the dosage form. Generally, the walls formed by thesetechnologies have a thickness of 2 to 20 mils (0.051 to 0.510 mm) with apresently preferred thickness of 2 to 10 mils (0.051 to 0.254 mm).

The dosage form of the invention in another embodiment is manufacturedby standard manufacturing techniques. For example, in one manufacturethe beneficial drug and other ingredients comprising a therapeuticcomposition or comprising the drug layer facing the exit means areblended, or the ingredients are blended then pressed, into a solidlayer. The drug and other ingredients can be blended with a solvent andformed into a solid or semisolid formed by conventional methods such asball-milling, calendaring, stirring or roll-milling and then pressedinto a selected shape. The drug layer posses dimensions that correspondto the internal dimensions of the area the drug layer is to occupy inthe dosage form. Next, the drug layer is placed in contact with thepush-displacement layer prepared in a like manner. The layering of thedrug layer and the push-displacement layer can be fabricated byconventional press-layering techniques. The membrane system possessesdimensions corresponding to the dimensions of the internal compartmentof the dosage form. Finally, the two-layer compartment forming membersare surrounded and coated with an inner and outer walls. A passageway islaser drilled or mechanically drilled through the walls to contact thedrug layer, with the dosage form optically oriented automatically by thelaser equipment for forming the passageway on the preselected drugsurface.

In another manufacture, the dosage form is manufactured by the wetgranulation technique. In the wet granulation technique the drug and theingredients comprising the drug layer are blended using a solvent, suchas isopropyl alcohol as the granulation fluid. Other granulating fluid,such as water, or denatured alcohol 100% can be used for this purpose.The ingredients forming the drug layer are individually passed through a40 mesh screen and then thoroughly blended in a mixer. Next, otheringredients comprising the layer are dissolved in a portion of thegranulation fluid, such as the solvent described above. Then, the latterprepared wet blend is slowly added to the drug blend with continualmixing in the blender. The granulating fluid is added until a wet blendmass is produced, which wet mass is then forced through a 20 mesh screenonto oven trays. The blend is dried for 18 to 24 hours at 25° C. to 40°C. The dry granules are then screened with a 16 mesh screen. Next, alubricant is passed through a 60 mesh screen and added to the dryscreened granule blend. This procedure is followed for thepush-displacement composition. The granulation in both instances, areput into mixing containers and tumble mixed for 2 to 10 minutes. Thedrug and the push composition are layered and pressed into a layeredtablet, for example in a Manesty® layer press.

Another manufacturing process that can be used for providing the drugand push-displacement compositions comprise blending their powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for example,poly(vinylpyrrolidone) in a solvent, such as in water, is sprayed ontothe respective powders. The coated powders are then dried in agranulator. This process coats the ingredients present therein whilespraying the granulating fluid. After the granules are dried, alubricant, such as stearic acid or magnesium stearate, is blended asabove into the mixture. The granules are then pressed in the mannerdescribed above. In another embodiment, when the fluid in granulatingprocess is used to manufacture the push-displacement layer, anantioxidant present in the polyalkylene oxide can be removed during theprocessing step. If antioxidant is desired, it can be added to thepush-displacement layer, and this can be accomplished during the fluidbed granulation described above.

The dosage form of this invention is manufactured in another embodimentby mixing a drug with composition-forming ingredients and pressing thecomposition into a solid layer possessing dimensions that correspond tothe internal dimensions of the compartment space adjacent to apassageway. In another embodiment, the drug and other drug compositionforming ingredients and a solvent are mixed into a solid, or semi-solid,by conventional methods such as ball-milling, calendaring, stirring, orroll-milling, and then pressed into a preselected, layer-forming shape.

In the general manufactures as presented herein, the manufacturecomprising a drug and compositional forming ingredients are placed incontact with the push-displacement layer, and the drug layer and thepush layers are surrounded then with the bilayered walls. The layeringof the drug composition and the push-displacement composition can beaccomplished by using a conventional two-layer tablet press technique.The walls can be applied by molding, spraying or dipping the pressedshapes into wall-forming materials. Another technique that can be usedfor applying the walls is the air-suspension wall-forming procedure.This procedure consists in suspending and tumbling the two layereddrug-push core in a current of air until the wall-forming compositionare applied separately to the compartment drug-push layers.Manufacturing procedures are described in Modern Plastics Encyclopedia,Vol. 46, pp. 62-70 (1969); and in Pharmaceutical Sciences, by Remington,14th ed., pp. 1626-1648 (1970) published by Mack Publishing Co., Easton,Pa. The dosage form can be manufactured by following the teaching theU.S. Pat. Nos. 4,327,725; 4,612,008; 4,783,337; 4,863,456; and4,902,514.

DETAILED DISCLOSURE OF EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure and the accompanying claims.

Example 1

The solubility of various hydrophilic materials to osmotic pressure wasevaluated. First, aqueous solutions of the hydrophilic materialhydroxypropyl-cellulose, commercially-available from Hercules,Wilmington, Del., under the trade name Klucel® were prepared usinggrades of different molecular weights. The solutions were prepared withmolecular weights of 80,000 grams per mole, 300,000 and 1 million gramsper mole using Klucel EF, GF and HF, respectively. An intermediatemolecular weight of 190,000 grams per mole was also generated byblending equal weight portions of the EF and GF grades. The resultingsolutions were then cast on glass plates and dried at room temperature.The resulting films were removed from the plates and a discs of 2.4 cm²area were punched from the films. Thicknesses of the discs were measuredwith a table micrometer. Four discs of each molecular weight type werethen individually bagged in nylon mesh bags having 12 openings per inchand attached to a plastic rod. The discs were then immersed inindividual solutions of the nonionic sugar, sorbitol, at concentrationsof 0, 182, 274, and 547 mg per milliliter thermostated to 37 degreescentigrade corresponding to a series of osmotic pressure values of 0,30, 48, and 125 atmospheres, respectively, and oscillated with afrequency of 30 cycles per minute at an amplitude of 2 centimeters. Theexperiment was conducted in 4 by 4 experimental matrix such that eachmolecular weight type was tested in each osmotic pressure reference. Thetime to dissolution was then monitored for each sample. Dissolution ratewas calculated according to Equation 5 and plotted as a function ofosmotic pressure for each molecular weight. The data are plotted in FIG.5. Based on these measurements, it was determined that thehydroxypropylcellulose having the lowest molecular weight of the seriesis insoluble above 30 atmospheres and soluble at an osmotic pressurebetween 0 and 30 atmospheres. This candidate hydrophilic material wasused in subsequent membrane formulations of the osmotically-sensitiveinterior wall of membrane system of the invention.

Example 2

A novel, therapeutic composition comprising hydromorphone andacetaminophen, wherein the hydromorphone is a member selected from thegroup consisting of hydromorphone pharmaceutically acceptable base andhydromorphone pharmaceutically acceptable salt is prepared as follows.First, 175 g of hydromorphone hydrochloride, 500 g of acetaminophen,647.5 g of poly(ethylene oxide) possessing a 100,000 molecular weight,and 43.75 g of poly(vinylpyrrolidone) having an average molecular weightof 40,000 are added to a mixing bowl and the ingredients dry mixed for10 minutes. Then, 331 g of denatured, anhydrous alcohol is added slowlyto the blended ingredients with continuous blending for 10 minutes.Next, the freshly prepared granulation is passed through a 20 meshscreen, allowed to dry at 25° C. for about 20 hours, and then passedthrough a 16 mesh screen. Next, the granulation is transferred to amixer, and lubricated with 8.75 g of magnesium stearate to produce atherapeutic hydromorphone acetaminophen composition. The therapeuticcomposition is compressed into tablets comprising 35 mg of hydromorphonehydrochloride and 100 mg of acetaminophen. The tablets are compressedunder 2 tons of pressure.

Example 3

The hydromorphone-acetaminophen analgesic tablets are coated with aninterior wall then coated by an exterior wall as follows. First, 154 gof ethyl cellulose having a molecular weight of 220,000 grams per moleand an ethoxyl content of 48.0 to 49.5 weight percent, and 112 g ofhydroxypropylcellulose having a 80,000 molecular weight and a molarsubstitution of 3, and then 14 g of polyoxyethylene (40) stearate weredissolved with stirring in 3,720 g of anhydrous ethanol. The solutionresulting was allowed to stand without stirring for 3 days, to providethe interior wall-forming composition. Next, the exterior wall formingcomposition was prepared by dissolving 162.5 g of cellulose acetatehaving an acetyl content of 39.8 wt % and a molecular weight of 40,000grams per mole, and 87.5 g of ethylene oxide-propylene oxide-ethyleneoxide triblock copolymer having a molecular weight of approximately8,400 grams per mole and an ethylene oxide content of 82 wt % in 4,750 gof anhydrous acetone with stirring and slight warming to 26° C. Theresulting exterior forming wall composition was allowed to stand atambient room temperature for one day.

Next, the analgesic tablets are placed into a pan coater. The interiorwall-forming solution was sprayed onto the tablets in a current of warmair until a wall with a thickness of 6 mils (0.152 mm) was applied tothe tablets. The interior ethylcellulose-hydroxypropylcellulose wallcoated tablets were dried in a forced air oven at 40° C. for 24 hrs.Then, the interior coated tablets were returned to the pan coater andthe exterior wall forming coat was sprayed onto the interior coatedtablet to a thickness of 3 mils (0.0762 mm). Next, the tabletscomprising the membrane system were dried and a round exit port having adiameter of 30 mils (0.762 mm) was drilled through the membrane systemto provide a controlled-extended release dosage form.

Example 4

Therapeutic compositions are manufactured by following the procedure ofExample 2, to provide analgesic compositions comprising 1 mg to 1000 mgof an opioid selected from the group consisting of hydromorphone,hydromorphone base, hydromorphone salt, and hydromorphone derivatives;at least one nonopioid analgesic of 1 to 1000 mg selected from the groupconsisting of acetaminophen, aspirin, flurbiprofen, ibuprofen,indoprofen, benoxaprofen, propoxyphene, salicylamide, zenazocine andzomepirac; with the dose of opioid and nonopioid analgesic in thecomposition comprising 2 mg to 1000 mg; at least one polymeric carrierfor both the opioid and nonopioid analgesics selected from 10 mg to 500mg of a poly(alkylene oxide) comprising a 100,000 to 500,000 molecularweight represented by poly(methylene oxide), poly(ethylene oxide),poly(propylene oxide), poly(isopropylene oxide) and poly(butyleneoxide); or a polymeric carrier of 10 mg to 500 mg of a carboxymethylenehaving a 7,500 to 325,000 molecular weight represented by a memberselected from the group consisting of an alkali carboxymethylcellulose,and potassium carboxymethylcellulose, calcium carboxymethylcellulose,and potassium carboxymethylcellulose; 0.5 mg to 50 mg of a poly(vinyl)polymer possessing a 5,000 to 300,000 molecular weight as represented bypoly(vinyl pyrrolidone), copolymer of poly(vinyl pyrrolidone and vinylacetate), copolymer of poly(vinyl pyrrolidone and vinyl chloride),copolymer of vinyl pyrrolidone and vinyl fluoride), copolymer ofpoly(vinyl pyrrolidone and vinyl butyrate), copolymer of poly(vinylpyrrolidone and vinyl laurate) and copolymer of poly(vinyl pyrrolidoneand vinyl stearate); and 0 to 7.5 mg of a lubricant represented by amember selected from the group consisting of polyethylene glycolmagnesium stearate, calcium stearate, potassium oleate, sodium stearate,stearic acid, and sodium palmitate. The therapeutic opioid-nonopioiddual analgesic composition may contain other composition formingingredients, for example, colorants, compression aids such asmicrocrystallinecellulose, and binders such as starch. The analgesiccomposition can be compressed at a ⅛ to 3 ton-force to yield an orallyadministrable tablet.

Example 5

The therapeutic analgesic composition is manufactured into anextended-sustained-linear release dosage form by providing the analgesiccomposition with an interior wall, an exterior wall and a passageway asset forth in Example 2.

Example 6

A novel and useful therapeutic composition comprising 432 g of amorphine selected from the group consisting of morphine base, morphinepharmaceutically acceptable salt, pharmaceutically acceptable inorganicsalt, pharmaceutically acceptable organic salt, morphine hydrobromide,morphine hydrochloride, morphine mucate, morphine N-oxide, morphinesulfate, morphine acetate, morphine phosphate dibasic, morphinephosphate monobasic, morphine inorganic salt, morphine organic salt,morphine acetate trihydrate, morphine bi(heptafluorobutyrate), morphinebi(methylcarbamate), morphine bi(pentafluoropropionate), morphinebi(pyridine-3-carboxylate), morphine bi(trifluoroacetate), morphinebitartrate, morphine chlorhydrate, and morphine sulfate pentahydrate,and 600 g of an analgesic selected from the group consisting ofacetaminophen, aspirin, benoxaprofen, flurbiprofen, ibuprofen,indoprofen, propoxyphene, salicylamide, zenazocrine and zomepirac areblended with 963 g of poly(alkylene oxide) comprising a 300,000molecular weight and 90 g of poly(vinyl pyrrolidone) having an averagemolecular weight of 40,000 are added to a mixing bowl and dry mixed for12 minutes. Next, 404 g of denatured, anhydrous alcohol is slowly addedto the blended composition forming materials with continuous mixing for15 minutes. Then, the prepared granulation is passed through a 20 meshscreen, and allowed to dry at 25° C. for 18 hrs, and then passed througha 16 mesh screen. The screened granulation is transferred to a planetarymixer, and with constant blending 14.9 g of calcium stearate is added toproduce the therapeutic two analgesic composition. The composition iscompressed into tablets comprising 350 mg of the therapeutic compositionconsisting of 70 mg of opioid analgesic and 100 mg of nonopioidanalgesic and 180 mg of tablet forming materials. The tablets arecompressed under 2.5 tons of pressure to provide a sustained releaseanalgesic tablet.

Example 7

The therapeutic compositions provided above and comprising the opioidanalgesic and the nonopioid analgesic are coated with a biwallcomprising an interior wall, and exterior wall and an exit passage byfollowing the procedure of Example 2 to provide acontrolled-linear-extended zero-releasing dosage form indicated for themanagement of pain.

Example 8

A controlled release dosage form for once a day administration of thepotent opioid analgesic, morphine, was fabricated as follows. First, 350grams of morphine sulfate hexahydrate, 585 grams of polyoxyethylenehaving a molecular weight of approximately 200,000 grams per mole, and60 grams of polyvinyl pyrrolidone having a molecular weight of 40,000grams per mole were each passed through a stainless screen having 40wires per inch and then dry mixed. Anhydrous ethanol was added withmixing until a uniform damp mass formed. The damp mass was forcedthrough a screen having 20 wires per inch, forming granules which werethen air dried at 22.5° C. overnight. After drying the granules werepassed again through the 20 mesh screen forming free-flowing granules.Then, 4.5 grams of magnesium stearate and 0.5 grams of butylatedhydroxytoluene were passed through a screen with 60 wires per inch intothe granules. The resulting mixture was tumbled for 5 minutes to form ahomogenous blend, to produce a drug granulation.

In a separate process, 936.7 grams of polyoxyethylene having a molecularweight of approximately 7 million grams per mole, 50 grams ofhydroxypropyl methyl cellulose having a molecular weight of 11,300 gramsper mole and a hydroxypropyl content of 10 weight percent and a methoxylcontent of 29 weight percent, were individually passed through a screenwith a size of 40 wires per inch. Then, 10 grams of ferric oxide greenand 0.8 grams of butylated hydroxytoluene were passed through a screenwith 60 wires per inch into the bulk mixture. The resulting powders weremixed to a uniform blend. Then, anhydrous ethanol was added with mixingto produce a uniform damp mass. The damp mass was then forced through ascreen with 20 wires per inch and air dried at ambient room conditions,22° C., overnight. The dried granules were then forced through the 20mesh screen. Finally, 2.5 grams of magnesium stearate, 0.8 grams ofbutylated hydroxytoluene were passed through a screen with 60 wires perinch into the granules. The mixture was tumble mixed for 3 minutes toproduce a push-displacement composition.

Next, the membrane system tablets, comprising the morphine composition,and the push-displacement composition, were compressed on abilayer-tablet press with the above granulations using a 13/32 inch(10.3 mm) round tooling punch. First, 287 mg of drug granulation was fedinto the die cavity and lightly compacted. Then, 151 mg of the pushgranulation was added to the die cavity and laminated to the push layerwith a force of 0.4 tons. Each of the resulting tablets contained a unitdoses of 100 mg morphine sulfate pentahydrate.

Next, the osmotic cores also referred to as bilayer cores, preparedimmediately above, were then coated with the laminated membrane of thisinvention according to the following procedures. First, 154 grams ofethyl cellulose having a molecular weight of approximately 220,000 gramsper mole and an ethoxyl content of 48.0 to 49.5 weight percent, 112grams of hydroxypropyl cellulose having a molecular weight of 80,000 anda molar substitution of 3 and 14 grams of polyoxyethylene (40) stearatewas dissolved in 3,720 grams of anhydrous ethanol formula with stirring.The resulting solution was allowed to stand without stirring for 3 days.This solution is referred to as the interior wall forming solution. Asecond solution was prepared by dissolving 162.5 grams of celluloseacetate having a acetyl content of 39.8 weight percent and anapproximate molecular weight of 40,000 grams per mole and 87.5 grams ofethylene oxide-propylene oxide-ethylene oxide triblock copolymer havingmolecular weight of approximately 8,600 grams per mole and an ethyleneoxide content of 82 weight percent in 4,750 grams of anhydrous acetonewith stirring and slight warming to 26 degrees centigrade. The resultingsolution is the exterior-wall forming solution and it was allowed tostand at ambient room temperature for one day.

The tablets were then charged into a pan coater. The interior-wallforming solution was sprayed onto the tablets in a current of warm airuntil a coating thickness of 9 mils was applied. The coating solutionwas stirred continuously while the tablets were being coated. The coatedtablets were then removed from the coating pan and dried in a forced airoven thermostated to 40 degrees centigrade for a day. Then, the tabletswere returned to the pan and the exterior wall forming solution wassprayed onto the dried tablets until a coating thickness of 3 mils wasapplied. The exterior wall forming solution was stirred continuouslyduring the coating process. After coating the tablets were removed fromthe coater and a delivery orifice was drilled through the laminatedwalls with a drill bit producing one round port having a diameter of 25mils in the center of the drug layer side of the tablet. The drilledsystems were then placed in a forced air drying oven thermostated to 50degrees centigrade for 3 days which drying completed the fabrication ofthe dosage form.

The dose release performance of the dosage forms prepared according tothis example were ascertained by measuring the dose release in distilledwater at 37° C. and as seen in the delivery pattern of FIG. 6. Themeasured results indicated a linear profile over 12 hrs at a constantrate of release of about 6 mg/hr during the corresponding time period.

The dosage form prepared according to this example with the resultsdepicted in FIG. 6 comprises: a drug layer composition comprising 35 wt% morphine sulfate pentahydrate, 58.50 wt % poly(ethylene oxide)possessing a 200,000 molecular weight, 6 wt % poly(vinyl pyrrolidone) of40,000 molecular weight, 0.45 wt % magnesium stearate, and 0.05 wt %butylated hydroxytoluene; a push-displacement composition comprising93.67 wt % poly(ethylene oxide) possessing a 7,000,000 molecular weight,5 wt % hydroxypropylmethylcellulose possessing a 11,200 molecularweight, 1 wt % green ferric oxide, 0.25 wt % magnesium stearate, and0.08 wt % butylated hydroxytoluene; an interior wall comprising 55 wt %ethylcellulose possessing a viscosity of 100 centipoises, 40 wt %hydroxypropyl-cellulose of 80,000 molecular weight, and 5 wt % Myrj 52Smanufactured by ICI Americas, Inc., Wilmington, Del. which representspolyoxyethylene (40) stearate; an exterior wall comprising 65 wt %cellulose acetate possessing a 39.8% acetyl content, and 35 wt %Pluronic F68 manufactured by BASF Corporation, Mt. Olive, N.J., whichrepresents a triblock copolymer of ethylene oxide-propyleneoxide-ethylene oxide having a molecular weight of approximately 8,400grams per mole with approximately 82 weight percent ethylene oxidecontent; a nominal time to deliver 80% of dose of 15.7 hrs; a meanrelease rate of 6.4 mg/hr; an exit port of 25 mil (0.635 mm), and a doseof drug of 100 mg; with the drug composition weighing 287 mg; thepush-displacement composition 151 mg, the interior wall 80.1 mg; and theexterior wall 26.9 mg; the interior wall was 8.8 mil (0.224 mm) thickand the exterior wall 2.6 mil (0.066 mm) thick.

Example 9

The present example is provided to illustrate the unexpected resultsobtained by this example. The dosage form of this example comprises asingle wall. The dosage form drug composition comprises the identicalcore composition as specified in Example 8 which is 35 wt % morphinesulfate pentahydrate, 58.50 wt % polyethylene oxide possessing a 200,000molecular weight, 6 wt % polyvinyl pyrrolidone possessing a 40,000molecular weight, 0.45 wt % magnesium stearate, and 0.05 wt % butylatedhydroxytoluene; a push-displacement composition comprising 93.97 wt %polyethylene oxide possessing a 7,000,000 molecular weight, 5 wt %hydroxypropylmethylcellulose possessing a 11,200 molecular weight, 1 wt% green ferric oxide, 0.25 wt % magnesium stearate, and 0.08 wt %butylated hydroxytoluene; a single wall comprising 92.0 wt % celluloseacetate possessing a 39.8% acetyl content, and 8 wt % polyethyleneglycol possessing a 3350 molecular weight; and a mean release rate of6.6 mg/hr. The single wall was formed from 80:20 (v:v) methyleneoxide:methanol. The results disputed in FIG. 7 indicated the dosage formdelivered drug for 16 hours at a nonzero order continuously decliningrate.

Example 10

The procedure set forth above was followed to manufacture a dosage formwith a drug composition comprising 35 wt % morphine sulfatepentahydrate, 58.5 wt % polyethylene oxide possessing a 200,000molecular weight, 6.0 wt % polyvinyl pyrrolidone of 40,000 molecularweight, 0.45 wt % magnesium stearate, and 0.05 butylated hydroxytoluene;a push-displacement composition comprising 93.97 wt % polyethylene oxidepossessing a 7,000,00 molecular weight, 5.0 wt %hydroxypropylmethylcellulose possessing a 11,200 molecular weight, 1 wt% green ferric oxide, 0.25 wt % magnesium stearate, and 0.08 wt %butylated hydroxytoluene; an inside wall comprising 55 wt % ethylcellulose having an ethoxyl content in the range of 48.0 to 49.5 weightpercent and a viscosity of 100 centipoise as a 5 percent solution at 25°centigrade in 80:20 toluene:ethanol, 20 wt % hydroxypropylcellulose ofmolecular weight 80,000 grams per mole as supplied as Klucel® EFmanufactured by Hercules Inc., Wilmington, Del., 20 wt % Kollidon 12 PFpolyvinylpyrrolidone manufactured by BASF, Ludwigshaften, West Germany,and 5 wt % Myrj 52S of approximately 2,060 grams per molecular weight(see Example 8); an outside wall comprising 65 wt % cellulose acetatehaving a 39.8% acetyl content, and 35 wt % Pluronic F68 (see Example 8);one 25 mil (0.635 mm) exit; and a mean release rate of 6.4 mg/hr. Thedosage form provided by this example exhibits the drug release profileseen in FIG. 8. The dosage form delivers drug at substantially zeroorderate earlier than the dosage form disclosed in Example 4 and itsdelivery profile attributed to the increase of pore forming polyvinylpyrrolidone in the interior wall.

Example 11

The present example provides a delivery system for delivering a narcoticanalgesic manufactured according to the examples set forth above, withthe drug delivered from the present example being a member selected fromthe group consisting of oxymorphone, hydromorphone, metopon,hydrocodone, levorphanol, phenazocine, methodone, dextromoramide,dipipanone, phenadoxone, codeine, dihydrocodeine, oxycodone, pholcodine,meperidine, levorphanol, phenazocine, methadone, dextromoramide,dipanone, phenodozone, meperidine, alphaprodine, anileridine, andpimiondone.

Example 12

An osmotic dosage form designed to deliver morphine at extended zeroorder rate was fabricated as follows. 330 grams of morphine sulfatehexahydrate and 610 grams of mannitol were dry blended and then passedthrough a screen with 40 wires per inch into the bowl of a planetarymixer. 50 grams of polyvinyl pyrrolidone having a molecular weight of9,000 grams per mole was dissolved with stirring in 500 milliliters ofanhydrous ethyl alcohol to form a binder solution. The binder solutionwas added slowly to the powders as they were mixed in the planetarymixer until a damp mass was formed. The damp mass was then passedthrough a screen with 20 wires per inch. The resulting extrusions wereair dried overnight at room temperature and then passed again through a20 mesh screen, thereby forming free-flowing granules. 10 grams ofmagnesium stearate sized through a 60 mesh screen was then tumble mixedinto the granules producing the finished granulation. The resultinggranulation was compressed with a force of 1.5 tons using with 11/32round standard concave tooling at a tablet weight 304 mg. Each tabletcontained a unit dose equivalent to 100 mg of morphine sulfatehexahydrate.

The tablets were then coated with an interior wall consisting of 55parts by weight of ethylcellulose having a molecular weight of 220,000grams per mole, 30 parts by weight of hydroxypropyl cellulose having amolecular weight of 80,000, 5 parts by weight of hydroxypropyl cellulosehaving a molecular weight of 300,000, 5 parts of polyvinyl pyrrolidonemolecular weight having a molecular weight of 1,300 grams per mole and 5parts of the ethylene oxide-propylene oxide-ethylene oxide triblockcopolymer having a nominal molecular weight of 7,700 grams per mole with72 weight percent of ethylene oxide supplied by BASF Corporation asPluronic F87. This composition was applied from a solution of ethylalcohol according to the procedures outlined in Example 8 to a thicknessof 5 mils. Then, an exterior wall was applied according to theprocedures in Example 8 by spray coating 3 mils of 70 parts celluloseacetate having an acetyl content of 39.8 weight percent and 40,000 gramsper mole and 30 parts polyethylene glycol having a molecular weight of400 from a solution of acetone. Two delivery ports were then drilled inthe system, one per side, centered in the round dome of the dosage form.Finally, the dosage form was dried for 3 days at 50° centigrade toremove residual coating solvents and establish equilibrium compositionof the coating. This resulted in a dosage form which when placed in anaqueous environment generated a internal osmotic pressure of 46atmospheres which remained constant while solid drug was present withinthe core. After the last bit of solid drug was dissolved, the osmoticpressure within the core declined to less than 30 atmospheres therebyallowing the pore formers of the internal wall to elute from the wall,thereby increasing wall permeability to compensate for the decreasing inosmotic driving force with the net effect to maintain elevated rate ofrelease of the analgesic for prolonged time.

Example 13

A dosage form which delivers the analgesic hydromorphone for once dailyadministration was fabricated as follows: 28.6 grams of hydromorphonehydrochloride and 50 grams of polyvinyl pyrrolidone having a molecularweight of 2,500 grams per mole were dissolved with stirring in 500milliliters of ethyl alcohol. 914 grams of sodium chloride was dried at50° C. in forced air overnight and then was passed through a sieve with40 wires per inch into a planetary mixer. The solution of drug was thenslowly added to the sodium chloride powder with stirring to form auniform damp mass. Two washings of ethanol were performed to completethe quantitative transfer of the drug into the damp mass. The damp masswas then passed through a mesh with 20 wires per inch, spread on a tray,and then oven dried overnight in forced air at 40° C. The dried materialwas then passed through a screen with 20 wires per inch, forming a freeflowing mixture. Finally, 7 grams of stearic acid was passed through ascreen with 80 wires per inch into the bulk mixture and tumble mixed for3 minutes, completing the granulation. The resulting granulation wascompressed at a force of 2 tons using ⅜ inch (9.5 mm) diameter roundtooling at a tablet weight of 280 milligrams. Each tablet contained aunit dose of 8 milligrams of the analgesic.

The tablets were then coated with an interior wall compositionconsisting of 55 parts of ethylcellulose having a molecular weight ofapproximately 118,000 grams per mole and an ethoxyl content of 48.0-49.5weight percent, 40 parts of the osmotically-sensitive pore former methylcellulose having a molecular weight of approximately 10,400 grams permole as supplied by the Dow Chemical Company, Midland, Mich. inMethocel™ A5, and 5 parts polyoxyethylene (50) stearate. The coatingfluid to apply this composition was prepared by dissolving the ethylcellulose and the polyoxyethylene (50) stearate in ethyl alcohol andthen dispersing the methyl cellulose in the resulting solution. Theresulting fluid was spray coated according to the procedures in Example8 to a wall thickness of 6 mils. Then, the exterior wall consisting of85 parts cellulose acetate with an acetyl content of 39.8 weight percentand a molecular weight of approximately 50,000 grams per mole and 15parts of the ethylene oxide-propylene oxide-ethylene oxide triblockcopolymer having a molecular weight of approximately 8,600 grams permole and a ethylene oxide content of 82 weight percent otherwisereferred to as Pluronic F87 were applied from a solution of acetoneaccording to the procedures in Example 8 to a uniform exterior wallthickness of 3 mils. Then, a 15 mil diameter port was laser drilledthrough both walls in the center of each side of the dosage from.Finally, the residual coating solvents were removed by drying in forcedair with 50% relative humidity at a temperature of 50° C. for 48 hoursfollowed by four hours at 50° C. without humidity.

When placed in an aqueous environment, water is imbibed by osmosis intothe dosage form dissolving the drug and salt to produce an internalosmotic pressure of 287 atmospheres and an ionic strength of 5.47 molarwhich osmotic pressure and ionic strength is maintained while the drugis dispensed until the last remaining portion of sodium chloridedissolves, at which point in time, the sodium chloride dilutes as aresult of the water continuing to flow into the dosage form to lowerlevels of osmotic pressure and ionic strength, thereby allowing the poreformer within the interior wall to dissolve and elute from the wall andthus increase permeability of the wall to compensate for the decrease inosmotic pressure as a result of the dilution. The dosage form meters therelease of 8 milligrams of the analgesic at controlled rate overprolonged time.

Example 14

An extended release dosage form of the analgesic hydrocodone for dosingonce a day dosing was prepared. 6,000 grams of hydrocodone bitartratehemipentahydrate and 19,000 grams of the osmotic agent glycine wereindividually milled to a particle size of less than 420 microns andcharged into a fluid bed granulator. Then, a binder solution wasprepared by dissolving of 130 grams of hydroxypropyl methylcellulosehaving a hydroxypropyl content of 10 weight percent, a methoxyl contentof 29 weight percent and a molecular weight of 11,300 grams per mole assupply under the product name Methocel E5 manufactured by DOW ChemicalCompany, Midland, Mich., in 2,470 milliliters of distilled water withstirring. The powders fluidized in a current of air and then the bindersolution was sprayed onto the fluidized powders in a current of warm airuntil to form granules. The granules were removed from the granulatorand transferred to a tote mixer where 30 grams of tablet lubricant,hydrogenated vegetable oil, was passed through a mesh with 60 wires perinch into the bulk granulation. The lubricant was mixed into the bulk bytumbling for 3 minutes. The resulting granulation was compressed withoval tooling at a compression force of 2 tons to an average tabletweight of 252 milligrams. Each tablet contained a unit dose of 60milligrams of the analgesic.

The resulting tablets were coated according to the procedures describedin Example 8. The interior wall consisted of 60 parts ethylcellulosehaving an ethoxyl content of 48.0-49.5 with a molecular weight ofapproximately 78,000 grams per mole, 34 parts hydroxypropyl cellulosehaving a molecular weight of approximately 80,000 grams per mole, 1 partdibutyl sebaccate, and 5 parts polyoxyethylene (8) stearate as suppliedin Myrj 45 manufactured by ICA Americas, sprayed from ethyl alcohol to acoating thickness of 6.5 mils. The exterior wall was applied accordingto the procedures detailed in Example 8. The coating consisted of 90parts cellulose acetate having an acetyl content of 39.8 weight percentand an average molecular weight of 30,000 grams per mole and 10 parts ofethylene oxide-propylene oxide-ethylene oxide triblock copolymer havingan ethylene oxide content of 83 weight percent and a molecular weight of14,600 grams per mole sprayed from acetone at 2.5 weight percent in theacetone to an exterior wall thickness of 2.5 mils. A 15-mil diameterdelivery port was then laser drilled on both sides of the dosage from.Fabrication was completed by drying in a forced air oven at 50° C. inforced air for 3 days to remove residual solvents.

When the resulting dosage form was placed in aqueous media, it imbibedwater across the bilayer wall coating under the osmotic gradient acrossthe membrane where the internal osmotic pressure was 90 atmospheres wasmaintained while solid drug and glycine were present, after which point,the osmotic pressure continuously declined in time. This processcontinued until the internal osmotic pressure declined to below 30atmospheres at which point the osmotically-sensitive pore formerhydroxypropyl cellulose eluted from the interior wall, therebyincreasing the permeability to compensate for the continuouslydecreasing osmotic driving force. The resulting dosage form delivered 60mg of the analgesic at controlled rate over prolonged time.

Example 15

The present example is provided to illustrate the unexpected resultsobtained by this example. An osmotic dosage form designed to deliver atherapeutic agent at extended ascending order rate was fabricated asfollows. 87.0 grams of metformin HCl, 7.0 grams of sodium chloride, 3.0grams of polyvinyl pyrrolidone, and 2.0 grams of poloxyethylene wereeach passed individually through a stainless wire screen having a meshsize of 40 wires per inch. The polyvinyl pyrrolidone had a molecularweight of approximately 360,000 grams per mole and is supplied asKollidon® 90 by the BASF Corporation, Ludwigshafen, West Germany. Thepolyethylene oxide had a molecular weight of approximately 5 million andis supplied as Polyox® Coagulant by the Union Carbide Corporation,Danbury, Conn. The components were well mixed in a beaker with a spatulato form a uniform blend. Ethyl alcohol anhydrous, formula SDA3A, wasadded to the blend with stirring until a uniform damp mass was formed.The damp mass was then forced with a spatula through a screen having 20wires per inch, forming elongated granules. The elongated granules wereair dried overnight at ambient room conditions. The dried granules werethen passed again though a 20-mesh sieve to form a free-flowinggranulation. 1.0 gram of stearic acid was tumble mixed into the blendfor 2 minutes. This process and composition formed the osmotic druglayer granulation.

A batch of tablets was made with the above-described granulation.Portions of the drug layer granulation, each weighing 977 mg, werecompressed with oval tablet tooling at a force of 2 tons. The major axisof the oval tablet was 19.7 mm and the minor axis was 10.6 mm. Eachtablet contained an 850 mg dose of the anti-diabetic drug, metforminHCl.

A subcoat solution was then prepared by dissolving 154 grams of EthylCellulose (EC), 56.0 grams of hydroxypropyl cellulose (HPC), 56.0 gramsof polyvinyl pyrrolidone, and 14.0 grams of polyoxyl 40 stearate in3,720 grams of SDA30 ethanol, anhydrous with stirring at roomtemperature. The EC was supplied by Dow Chemical, Midland, Mich., asEthocel Standard Premium 100 that had a ethoxyl content of 48.0-49.5weight percent and had a molecular weight of approximately 222,000. TheHPC was Klucel® EF, supplied by Aqualon of Wilmington, Del., and had amolecular weigh of approximately 80,000. The polyoxyl 40 stearate wassupplied by ICI Americas of Wilmington, Del. as Myrj® 52. The solutionwas allowed to stand for 3 days at room temperature prior to furtherprocessing.

An overcoat solution was prepared by dissolving 22.5 grams of poloxomer188 in 1425 grams of acetone with stirring and warming to 37° C. for0.25 hour. Then, 52.5 grams of cellulose acetate was dissolved into themix by stirring for 1 hour. The cellulose acetate had an acetyl contentof 39.8 weight percent and a molecular weight of approximately 40,000,supplied as CA 398-10 by Eastman Chemical of Kingsport, Tenn. Thesolution was allowed to stand overnight prior to further processing.

A portion of the osmotic drug tablets as described above were loadedinto a pharmaceutical pan coater. The subcoat solution was sprayed ontothe bed of tablets while it tumbled in a current of warm air until 40 mgof subcoat material was deposited onto the cores, representing a coatingthickness of 70 microns. Then, the overcoat solution was applied to thebed in like manner until a coating weight of 61 mg was deposited,representing a coating thickness of about 100 microns. A single port wasthen drilled across both coated layers using a mechanical drill bithaving a diameter of 500 microns. Finally, the drilled delivery systemswere dried in a forced air oven thermostated at 40° C. to removeresidual coating solvents.

Three of the resulting delivery systems were tested in vitro byattaching each system to a plastic rod with a small drop of Duco cement.The resulting systems were immersed in 45 ml of simulated gastric fluidthermostated at 37° C. and agitated gently for 1 hour. At that point,the systems were transferred to a fresh release receptor solution andthe test continued for another hour. This process was repeated until 16hours of testing was completed. The resulting release receptors wereanalyzed for drug content using an ultraviolet spectrometer and releaserate of drug as a function of time was plotted. This generated therelease pattern illustrated in FIG. 9, panel A. The system demonstratedan ascending release rate pattern that ascended in time during the first10 hours. The time to release 90% of the dose was between 14 and 15hours.

Another set of uncoated tablets from the above batch were coated with180 microns of the overcoat composition but without the subcoat layer.These systems were drilled, dried, and tested for release of drug. Thisprocess generated the release pattern illustrates in FIG. 9, panel B.The resulting release pattern was substantially non-ascending and had atime to deliver 90% of the dose of about 14 hours.

It clear from these pair of patterns that the subcoat layer provided thegradual and prolonged ascending release rate pattern that was absentwhen the subcoat layer was not present.

Method of Practicing Invention

The invention pertains additionally to the use of the therapeutic dosageform by providing a method for delivering a drug orally to awarm-blooded animal including a human patient in need of therapy. Themethod comprises administering orally the therapeutic dosage form intothe patient, wherein the dosage form comprises a therapeutic compositionsurrounded by an interior wall and a contacting exterior wall, or themethod comprises administering a dosage form comprising a therapeuticcomposition and a push composition with both compositions surrounded byan inside wall and an exterior wall. The dosage form, in both methods ofuse, in the gastrointestinal tract imbibes fluid through both wall,generates osmotic energy, that causes the therapeutic composition to beadministered through an exit port up to 30 hours to provide controlledand sustained therapy.

In summary, it will be appreciated that the present inventioncontributed to the art an unobvious dosage form that possesses practicalutility, and can administer a drug at a dose-metered release rate perunit time. While the invention has been described and pointed out indetail with reference to operative embodiments thereof, it will beunderstood by those skilled in the art that various changes,modifications, substitution and omissions can be made without departingfrom the spirit of the invention. It is intended, therefore, that theinvention embrace those equivalents within the scope of the claims whichfollow.

1-45. (canceled)
 46. A therapeutic solid, sustained-release compositioncomprising an opioid analgesic, a nonopioid analgesic, and apharmaceutically acceptable carrier, wherein the opioid analgesiccomprises a member selected from the group consisting of hydrocodone andits pharmaceutically acceptable salts and the nonopioid analgesiccomprises acetaminophen.
 47. The therapeutic composition of claim 46,wherein the pharmaceutically acceptable carrier is polyethylene oxidecarrier.
 48. The therapeutic composition of claim 46, which comprisespolyvinyl pyrrolidone.
 49. The therapeutic composition of claim 46,wherein the pharmaceutically acceptable carrier comprisescarboxyalkylcellulose.
 50. The therapeutic composition of claim 46,which is coated with a wall comprising ethylcellulose andhydroxypropylcellulose.
 51. The therapeutic composition of claim 46,which is coated with a wall comprising cellulose acetate.
 52. Thetherapeutic composition of claim 46, which is coated with a laminatecomprising a lamina comprising ethylcellulose and hydroxypropylcelluloseand a lamina comprising cellulose acetate.
 53. The therapeuticcomposition of claim 46, which comprises 1 mg to 1000 mg of the opioidanalgesic and 1 mg to 1000 mg of the nonopioid analgesic.
 54. Acontrolled release dosage form comprising: an osmotic core comprising ananalgesic composition; an interior wall surrounding at least a portionof said osmotic core, wherein fluid permeability of the interior wall isresponsive to osmolarity of said osmotic core; and a fluid-permeableexterior wall surrounding the interior wall.
 55. The controlled releasedosage form of claim 54, wherein the analgesic composition comprises anopioid analgesic.
 56. The controlled release dosage form of claim 55,wherein the opioid analgesic comprises hydrocodone.
 57. The controlledrelease dosage form of claim 55, wherein the analgesic compositionfurther comprises a nonopioid analgesic.
 58. The controlled releasedosage form of claim 57, wherein the nonopioid analgesic is selectedfrom the group consisting of acetaminophen, aspirin, benoxaprofen,flurbiprofen, ibuprofen, indoprofen, propoxyphene, salicylamide,zenazocine and zomepirar.
 59. The controlled release dosage form ofclaim 57, wherein the opioid analgesic comprises hydrocodone and thenonopioid analgesic comprises acetaminophen.
 60. The controlled releasedosage form of claim 57, wherein the analgesic composition furthercomprises a pharmaceutically acceptable carrier for both the opioidanalgesic and nonopioid analgesic.
 61. The controlled release dosageform of claim 60, wherein the pharmaceutically acceptable carrier ispolyethylene oxide carrier.
 62. The controlled release dosage form ofclaim 60, wherein the analgesic composition comprises polyvinylpyrrolidone.
 63. The controlled release dosage form of claim 54, whereinthe interior wall comprises ethyl cellulose and hydroxypropylcellulose.64. The controlled release dosage form of claim 54, wherein the exteriorwall comprises cellulose acetate.
 65. The controlled release dosage formof claim 54, wherein the internal wall and the external wall act inconcert to provide a controlled delivery of the analgesic compositionover an extended or sustained-release period of time.
 66. The controlledrelease dosage form of claim 54, wherein the analgesic composition isdelivered over a period of about 30 minutes to about 24 hours.
 67. Thecontrolled release dosage form of claim 54, wherein the analgesiccomposition is delivered over a period of about 4 hours to about 24hours.
 68. The controlled release dosage form of claim 54, wherein theinterior wall comprises a hydrophobic substance and a hydrophilicsubstance and the exterior wall is semipermeable.
 69. The controlledrelease dosage form of claim 68, wherein hydrophilicity of thehydrophilic substance is osmosensitive.
 70. The controlled releasedosage form of claim 68, wherein the hydrophilic substance exhibits anaqueous solubility responsive to osmotic pressure and/or ionic strengthof the osmotic core.
 71. The controlled release dosage form of claim 68,wherein the hydrophilic substance provides increased permeability of theinterior wall in response to a decrease in the osmotic pressure and/orionic strength of the osmotic core.
 72. The controlled release dosageform of claim 68, wherein the hydrophobic substance comprises ethylacetate or cellulose acetate, the hydrophilic substance compriseshydroxyalkylcellulose, and the semipermeable substance comprisescellulose acetate.